CN116173018A - Darotamine pharmaceutical composition and preparation method and application thereof - Google Patents

Darotamine pharmaceutical composition and preparation method and application thereof Download PDF

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Publication number
CN116173018A
CN116173018A CN202111422274.6A CN202111422274A CN116173018A CN 116173018 A CN116173018 A CN 116173018A CN 202111422274 A CN202111422274 A CN 202111422274A CN 116173018 A CN116173018 A CN 116173018A
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Prior art keywords
pharmaceutical composition
compositions
formulation
darostaamine
carrier material
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CN202111422274.6A
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Inventor
钱晓明
施瑜
李坤
万建胜
盛小茜
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Shanghai Xuantai Pharmaceutical Technology Co ltd
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Shanghai Xuantai Pharmaceutical Technology Co ltd
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Priority to CN202111422274.6A priority Critical patent/CN116173018A/en
Priority to PCT/CN2022/132894 priority patent/WO2023093640A1/en
Publication of CN116173018A publication Critical patent/CN116173018A/en
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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Abstract

The invention relates to a pharmaceutical composition comprising the active ingredient darostamine or a pharmaceutically acceptable salt thereof, a carrier material and a formulation improving agent. The invention also relates to a solid formulation comprising the pharmaceutical composition of the invention. The invention also relates to a method for preparing the pharmaceutical composition and the solid preparation.

Description

Darotamine pharmaceutical composition and preparation method and application thereof
Technical Field
The invention relates to a darostaamine pharmaceutical composition, a preparation method and application thereof.
Background
Darolutamide (Darolutamide) has the chemical name N- [ (1S) -2- [3- (3-chloro-4-cyanophenyl) -1H-pyrazol-1-yl ] -1-methylethyl ] -5- (1-hydroxyethyl) -1H-pyrazole-3-carboxamide, and its chemical structure is shown below.
Figure BDA0003377915050000011
Darostaamine is an oral non-steroidal Androgen Receptor (AR) inhibitor suitable for use in the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC) patients. In 2019, darostamine developed by bayer corporation was approved by the united states Food and Drug Administration (FDA) for marketing. In addition, phase III clinical trials of darostaamine showed that darostaamine in combination with ADT significantly prolonged median Metastasis Free Survival (MFS) (18.4 months vs 40.4 months) compared to placebo in combination with androgen deprivation therapy (androgen deprivation therapy, ADT) and reduced the risk of disease metastasis or death by 59% while also having good safety.
Darotamine is a low-solubility, high-permeability drug (BCS class II) that is substantially insoluble (14-23 μg/mL) in aqueous media at pH 1-6.8. Single dose pharmacokinetic studies showed the median T of darostamine max For 3-6 hours, it was shown that its absorption was slow. The terminal half-life of darostamine is 10-15 hours. C at 600mg dose administered in fasted and fed state max AUC (all over the air) (0-t) Above 300mg. And for AUC (0-t) The coefficient of variation (CV%) of 300mg (69.6%) was administered in an amount of more than 600mg (41.4%).
In addition, the bioavailability of 300mg of darostaamine administered in the fasted state was about 30%. While in the fed state, the bioavailability of 300mg or 600mg of darostamine is improved by 2.5 times and 2.8 times respectively after single dose administration. Similarly, in the fed state, AUC of 300mg or 600mg of darostaamine was administered (0-t) The improvement is 2.5 times. It can be seen that there is a pronounced food effect of darostamine.
WO2019032840A1 discloses a pharmaceutical composition comprising abiraterone acetate and darostaamine, said pharmaceutical composition further comprising polyvinylpyrrolidone or a vinylpyrrolidone/vinyl acetate copolymer as a first pharmaceutical excipient and sodium lauryl sulfate as a second pharmaceutical excipient. The inventors claim that the pharmaceutical composition has increased in vitro permeability in fasted and fed states, thereby enabling a reduction of the drug dosage, avoiding the limitation of fasting consumption. The inventors have not confirmed the technical effects described above by examples.
Disclosure of Invention
In one aspect, the present invention relates to a pharmaceutical composition comprising the active ingredient darostamine or a pharmaceutically acceptable salt thereof, a carrier material, and a formulation modifying agent, wherein the formulation modifying agent is one or more selected from the group consisting of: sodium lauryl sulfate, polyethylene glycol vitamin E succinate, poloxamer, polyoxyethylene hydrogenated castor oil, stearyl alcohol, dibutyl sebacate, triethyl citrate, butyl citrate, glycerin, polyethylene glycol, lecithin, sodium dioctyl sulfosuccinate, sodium taurocholate, polysorbate, polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, and polyoxyethylene castor oil; the carrier material is one or more selected from the following: hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl methylcellulose acetate succinate, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, ewing, copovidone, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropyl cellulose, polyvinyl acetate, cyclodextrin, sodium carboxymethyl ethylcellulose polyethylene oxide, cellulose acetate phthalate, cellulose acetate trimellitate.
In one embodiment, the weight ratio of active ingredient darostaamine or a pharmaceutically acceptable salt thereof to carrier material is from about 1:0.5 to 1:8.
In one embodiment, the weight ratio of active ingredient darostaamine or a pharmaceutically acceptable salt thereof to formulation modifying agent is about 1:0.05 to 1:0.8.
In another aspect, the present invention relates to a solid formulation comprising the pharmaceutical composition of the present invention.
In a further aspect, the present invention relates to a method of preparing a pharmaceutical composition of the present invention comprising the steps of: (1) weighing the components; (2) Mixing the components of step (1) and hot melt extrusion to obtain a pharmaceutical composition.
In a further aspect, the present invention relates to a method for preparing a solid formulation according to the present invention, comprising the steps of: (1) preparing a pharmaceutical composition according to the above method; (2) Comminuting the pharmaceutical composition of step (1) to obtain pharmaceutical composition particles; (3) Mixing the pharmaceutical composition particles of step (2) with a lubricant and other formulation modifiers to obtain total mixed particles; (4) The total mixed granules of step (3) are pressed to obtain a solid formulation.
In a further aspect, the present invention relates to the use of the pharmaceutical composition and solid formulation of the present invention for the manufacture of a medicament for the treatment or prevention of prostate cancer.
Detailed Description
The present invention will be described in further detail below. Such description is for the purpose of illustration and not limitation. Other advantages and effects of the present invention will be readily apparent to those skilled in the art from the disclosure herein. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways. Various modifications and alterations may be made by those skilled in the art without departing from the spirit of the invention.
General definitions and terms
All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety, if not indicated otherwise.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event of a conflict, the definitions provided herein will control.
All percentages, parts, ratios, etc. are by weight unless otherwise specified.
When an amount, concentration, or other value or parameter is given as either a range, preferred range or upper and lower limit or a particular value, this is to be understood as specifically disclosing all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether ranges are separately disclosed. When numerical ranges are recited herein, unless otherwise stated, the stated ranges are meant to include the endpoints thereof, and all integers and fractions within the range. The scope of the invention is not limited to the specific values recited when defining the scope. For example, "1-20" encompasses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 and any subrange comprised of any two values therein, e.g., 2-6, 3-5, 2-10, 3-15, 4-20, 5-19, etc.
The terms "about", "about" when used in conjunction with a numerical variable generally refer to the value of the variable and all values of the variable being within experimental error (e.g., within a confidence interval of 95% for the average) or within + -10% of the specified value, or more broadly.
The term "metering ratio" is to mix various substances according to a certain weight. For example, in the present invention, the active ingredient is mixed with the filler, binder and lubricant in a prescribed weight ratio.
The term "selected from …" means that one or more elements in the group listed below are independently selected and may include a combination of two or more elements.
The terms "one or more" or "at least one" as used herein mean one, two, three, four, five, six, seven, eight, nine or more.
Unless otherwise indicated, the terms "combination thereof" and "mixtures thereof" refer to multicomponent mixtures of the elements, e.g., two, three, four, and up to the maximum possible multicomponent mixtures.
Furthermore, the number of components or groups of components of the present invention not previously indicated is not limiting with respect to the number of occurrences (or existence) of components or groups of components. Thus, the singular forms of a component or a constituent should be interpreted to include one or at least one, and the plural unless the numerical value clearly indicates the singular.
The term "optional" or "optionally" as used herein means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps. Those skilled in the art will appreciate that such terms as "comprising" encompass the meaning of "consisting of …". The expression "consisting of …" excludes any element, step or ingredient not specified. The expression "consisting essentially of …" means that the scope is limited to the specified elements, steps, or components, plus any elements, steps, or components that are optionally present that do not materially affect the basic and novel characteristics of the claimed subject matter. It should be understood that the expression "comprising" encompasses the expressions "consisting essentially of …" and "consisting of …".
The term "pharmaceutically acceptable" refers to those compositions which, within the scope of normal medical judgment, are in contact with the tissues of a patient without undue toxicity, irritation, allergic response, and the like, are commensurate with a reasonable benefit-to-benefit ratio, and are effective for their intended use.
The term "pharmaceutically acceptable excipients" refers to those carrier materials which do not significantly stimulate the organism and which do not impair the biological activity and properties of the active compound. "pharmaceutically acceptable excipients" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, disintegrants, stabilizers, solvents or emulsifiers. Non-limiting examples of such carriers include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, and the like. For additional information on the vector, reference may be made to Remington, the Science and Practice of Pharmacy,21st Ed., lippincott, williams & Wilkins (2005), the contents of which are incorporated herein by reference.
The term "pharmaceutically active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating or preventing a disease or condition of interest.
The term "effective amount", "therapeutically effective amount" or "prophylactically effective amount" with respect to a drug, drug unit or active ingredient refers to a sufficient amount of a drug or agent that is acceptable for side effects but achieves the intended effect. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.
The term "tablet" refers to a solid pharmaceutical dosage form comprising the active ingredient, and optionally, suitable excipients, such as diluents, binders, and the like, and prepared by compression or molding techniques. Examples of tablets are compressed tablets, multiparticulate tablets, coated tablets, matrix tablets, osmotic pump tablets, and tablets (caplets), and the like.
The term "bulk density" refers to the mass of an amount of particulate product divided by the total volume occupied by the amount.
The term "angle of repose" refers to the maximum angle formed by the free slope of the powder build-up and the horizontal plane. The smaller the angle of repose, the smaller the friction and the better the flowability.
The term "dissolution" refers to the rate and extent of dissolution of a drug from a solid formulation in a defined solvent.
Pharmaceutical composition
In one aspect, the present invention relates to a pharmaceutical composition comprising the active ingredient darostamine or a pharmaceutically acceptable salt thereof, a carrier material and a formulation modifying agent.
Active ingredient
In one embodiment, the active ingredient is darostaamine or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the active ingredient is darostaamine.
Carrier material
By carrier material is meant a material, typically in particulate form, for carrying an active ingredient, wherein the active ingredient is substantially distributed in the carrier material.
In one embodiment, the carrier material is one or more selected from the group consisting of: hydroxypropyl methylcellulose phthalate (Hydroxypropylmethyl cellulose phthalate, HPMCP), hydroxypropyl methylcellulose (Hydroxypropyl methylcellulose, HPMC), polyvinyl alcohol (Polyvinyl alcohol, PVA), polyvinylpyrrolidone (Polyvinyl pyrrolidone, PVP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (e.g.)
Figure BDA0003377915050000061
) Special (e.g.)
Figure BDA0003377915050000062
) Povidone, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropyl cellulose, polyvinyl acetate, cyclodextrin and carboxymethylSodium ethylcellulose polyethylene oxide, cellulose acetate phthalate, cellulose acetate trimellitate. In a preferred embodiment, the carrier material is one or more selected from the group consisting of: hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose acetate succinate, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and Uttky. Suitable carrier materials help to increase the solubility of the pharmaceutical composition.
As examples, carrier materials that may be used include, but are not limited to, the commercial products of Shin-Etsu corporation
Figure BDA0003377915050000063
(HPMCAS), commercially available product of BASF company->
Figure BDA0003377915050000064
VA64 and->
Figure BDA0003377915050000065
PVP K30, a commercial product of Ashland, inc.
Agent for improving agent
In one embodiment, the formulation modifying agent is one or more selected from the group consisting of: sodium lauryl sulfate, polyethylene glycol vitamin E succinate, poloxamer, polyoxyethylene hydrogenated castor oil, stearyl alcohol, dibutyl sebacate, triethyl citrate, butyl citrate, glycerin, polyethylene glycol, lecithin, sodium dioctyl sulfosuccinate, sodium taurocholate, polysorbate, polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, and polyoxyethylene castor oil. In a preferred embodiment, the formulation modifying agent is one or more selected from the group consisting of: sodium dodecyl sulfate, vitamin E succinic acid polyethylene glycol ester triethyl citrate.
By way of example, formulation modifiers that may be used include, but are not limited to, the commercially available products of PMC Isochem, VE TPGS1000, BASF
Figure BDA0003377915050000066
A commercially available TEC product from the company SLS, merck KGaA.
In the art, sodium dodecyl sulfate, polyethylene glycol vitamin E succinate, poloxamer, polyoxyethylene hydrogenated castor oil, stearyl alcohol, dibutyl sebacate, triethyl citrate, butyl citrate, glycerin, polyethylene glycol, lecithin, sodium dioctyl sulfosuccinate, sodium taurocholate, polysorbate, polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene castor oil and the like are generally used as surfactants or plasticizers of solid preparations, etc., for example, the coating film of the coated tablet can be made softer, so that the coated tablet is not easily cracked, and easy to store and transport. The inventors have surprisingly found that the formulation improvers used in the present invention can achieve unexpected technical effects, such as further increasing the solubility of the pharmaceutical composition, thereby increasing the bioavailability of the drug, increasing the stability of the drug, making the pharmaceutical composition easy to prepare, thereby saving energy consumption for production.
In one embodiment, in the pharmaceutical composition of the invention, when the formulation modifying agent is polyethylene glycol, the carrier material is not polyvinylpyrrolidone and/or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and/or hydroxypropyl cellulose.
In one embodiment, in the pharmaceutical composition of the present invention, when the formulation modifying agent is sodium lauryl sulfate, the carrier material is not polyvinylpyrrolidone and/or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and/or hydroxypropyl cellulose.
In one embodiment, in the pharmaceutical composition of the invention, when the formulation modifying agent is a poloxamer, the carrier material is not polyvinylpyrrolidone and/or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and/or hydroxypropyl cellulose.
In one embodiment, in the pharmaceutical composition of the present invention, when the formulation modifier is two or three of polyethylene glycol, sodium dodecyl sulfate, and poloxamer, the carrier material is not polyvinylpyrrolidone and/or polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and/or hydroxypropyl cellulose.
In one embodiment, in the pharmaceutical composition of the invention, when the formulation modifying agent is polyethylene glycol, sodium lauryl sulfate or poloxamer, the carrier material is not polyvinylpyrrolidone and/or polyvinylcaprolactam-partial vinyl acetate-polyethylene glycol graft copolymer and/or hydroxypropylcellulose.
In other words, when the formulation modifier used is polyethylene glycol, sodium lauryl sulfate, poloxamer, or a combination thereof, the carrier material is not polyvinylpyrrolidone, is not a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, is not hydroxypropyl cellulose, or is a combination of two or more of the foregoing.
In a preferred embodiment, in the pharmaceutical composition of the present invention, the formulation modifying agent is one or more selected from the group consisting of: sodium dodecyl sulfate, vitamin E succinic acid polyethylene glycol ester, dibutyl sebacate, triethyl citrate, butyl citrate, glycerol and polyethylene glycol; the carrier material is one or more selected from the following: hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl methylcellulose acetate succinate, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, ewing, copovidone, methylcellulose, ethylcellulose, sodium carboxymethylcellulose; wherein when the formulation modifying agent is sodium lauryl sulfate or polyethylene glycol, the carrier material is not polyvinylpyrrolidone and/or a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.
In a more preferred embodiment, in the pharmaceutical composition of the present invention, the formulation modifying agent is one or more selected from the group consisting of: sodium dodecyl sulfate, vitamin E succinic acid polyethylene glycol ester, triethyl citrate; the carrier material is one or more selected from the following: hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose acetate succinate, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, among others; wherein when the formulation modifying agent is sodium lauryl sulfate, the carrier material is not polyvinylpyrrolidone and/or a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.
In a specific embodiment, in the pharmaceutical composition of the present invention, the formulation modifier is vitamin E polyethylene glycol succinate and the carrier material is hydroxypropyl methylcellulose acetate succinate. In a specific embodiment, in the pharmaceutical composition of the present invention, the formulation modifying agent is polyvinylpyrrolidone and the carrier material is hydroxypropyl methylcellulose acetate succinate. In a specific embodiment, in the pharmaceutical composition of the present invention, the formulation modifier is vitamin E polyethylene glycol succinate and the carrier material is hydroxypropyl methylcellulose acetate succinate and polyvinylpyrrolidone. In a specific embodiment, in the pharmaceutical composition of the present invention, the formulation modifying agent is triethyl citrate and the carrier material is eudragit.
Other components
In one embodiment, the pharmaceutical composition of the present invention may further comprise pharmaceutically acceptable excipients.
In one embodiment, the pharmaceutical composition of the present invention may further comprise one or more selected from the group consisting of: buffering agents, acidifying agents, stabilizers, preservatives.
Buffering agents
Buffers refer to pharmaceutically acceptable excipients that stabilize the pH of the pharmaceutical formulation.
In one embodiment, the buffer is one or more selected from the group consisting of: citric acid buffer, malate buffer, maleate buffer, tartrate buffer.
Acidulant
Acidulant refers to an acid that is used primarily as an adjunct in the preparation of a drug, which is used to adjust the pH of the drug, and which provides only acidity upon use, usually without introducing specific biological activity.
In one embodiment, the acidulant is one or more selected from the group consisting of: tartaric acid, carbonic acid, acetic acid, oxalic acid and nitrous acid.
Stabilizing agent
Stabilizers refer to specific chemicals that interact with the active ingredient and/or general pharmaceutical excipients in the pharmaceutical composition to improve its stability.
In one embodiment, the stabilizer is one or more selected from the group consisting of: methionine, lysine, histidine.
Preservative agent
Preservatives refer to compounds added to pharmaceutical compositions to prevent or delay microbial activity (growth and metabolism).
In one embodiment, the preservative is one or more selected from the group consisting of: benzyl alcohol, benzyl benzoate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, vitamin E, and vitamin A palmitate.
In one embodiment, the weight ratio of active ingredient darostaamine or a pharmaceutically acceptable salt thereof to carrier material is from about 1:0.5 to 1:8. In a preferred embodiment, the weight ratio of active ingredient darostaamine or a pharmaceutically acceptable salt thereof to carrier material is from about 1:1 to about 1:4. In a more preferred embodiment, the weight ratio of the active ingredient darostaamine or a pharmaceutically acceptable salt thereof to the carrier material is from about 1:2 to about 1:4. Such as about 1:0.5, about 1:0.8, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, and ranges consisting of any two of these ratios (values). The appropriate weight ratio of active ingredient to carrier material is advantageous in achieving the appropriate solubility and dissolution. Too high a weight ratio of active ingredient to carrier material may not be effective in increasing the solubility of the active ingredient; too low a weight ratio of active ingredient to carrier material will not increase the solubility of the active ingredient more effectively and will cause excessive viscosity of the solid formulation, resulting in difficulty in its preparation.
In one embodiment, the weight ratio of active ingredient darostaamine or a pharmaceutically acceptable salt thereof to formulation modifying agent is about 1:0.05 to 1:0.8. In a preferred embodiment, the weight ratio of the active ingredient darostaamine or a pharmaceutically acceptable salt thereof to the formulation modifying agent is from about 1:0.1 to about 1:0.5. Such as about 1:0.05, about 1:0.1, about 1:0.15, about 1:0.2, about 1:0.25, about 1:0.3, about 1:0.35, about 1:0.4, about 1:0.45, about 1:0.5, and ranges consisting of any two of these ratios (values). The proper weight ratio of the active ingredient to the preparation modifier is favorable for obtaining proper solubility, solubility and stability, and the obtained medicine is easy to store and absorb by human body. Too high a weight ratio of active ingredient to formulation modifier may not be effective in increasing the solubility of the active ingredient; too low a weight ratio of active ingredient to formulation modifier will not increase the solubility of the active ingredient more effectively, but rather will not result in preparation.
Bulk density of
Bulk density is the bulk density, which refers to the mass of the particles of the pharmaceutical composition of the present invention divided by the volume it occupies. The proper bulk density is beneficial to the preparation of the pharmaceutical composition and the preparation products thereof, and further is beneficial to obtaining the products with proper solubility and dissolution.
In one embodiment, the bulk density of the pharmaceutical composition is about 0.40-0.50g/mL. In a preferred embodiment, the bulk density of the pharmaceutical composition is about 0.42-0.49g/mL. In a more preferred embodiment, the pharmaceutical composition has a bulk density of about 0.436-0.473g/mL. Such as about 0.40g/mL, 0.41g/mL, 0.42g/mL, 0.423g/mL, 0.425g/mL, 0.427g/mL, 0.429g/mL, 0.43g/mL, 0.433g/mL, 0.436g/mL, 0.439g/mL, 0.44g/mL, 0.442g/mL, 0.445g/mL, 0.448g/mL, 0.45g/mL, 0.451g/mL, 0.46g/mL, 0.466g/mL, 0.469g/mL, 0.47g/mL, 0.473g/mL, 0.48g/mL, 0.49g/mL.
Angle of repose
The angle of repose refers to the maximum angle formed by the free slope of the accumulation of particles of the pharmaceutical composition of the present invention and the horizontal plane. Wherein, the smaller the angle of repose, the smaller the friction force between the particles of the pharmaceutical composition of the present invention, i.e. the better the flowability of the pharmaceutical composition particles. The suitable angle of repose of the particles of the pharmaceutical composition facilitates the preparation of the formulation product, and thus facilitates the obtaining of a formulation product having suitable solubility and dissolution.
In one embodiment, the angle of repose of the pharmaceutical composition is about 20-32 °. In a preferred embodiment, the angle of repose of the pharmaceutical composition is about 21-30 °. In a more preferred embodiment, the angle of repose of the pharmaceutical composition is about 22-28 °. Such as about 20 °, about 21 °, about 22 °, about 23 °, about 24 °, about 25 °, about 26 °, about 27 °, about 28 °, about 29 °, about 30 °, about 31 °, about 32 °.
Solid preparation
In another aspect, the present invention relates to a solid formulation comprising the pharmaceutical composition of the present invention.
The preparation method of the invention
Preparation of pharmaceutical compositions
In another aspect, the present invention relates to a method of preparing a pharmaceutical composition of the present invention comprising the steps of:
(1) Weighing the components;
(2) Mixing the components of step (1) and hot melt extrusion to obtain a pharmaceutical composition.
Wherein the active ingredient, carrier material and formulation modifier are as defined above.
Step (1)
The individual components of the pharmaceutical composition are weighed according to a specific metering ratio (e.g., weight ratio). The individual components of the pharmaceutical compositions may be weighed, for example, according to the weight ratios in the examples below.
Step (2)
The hot melt extrusion of step (2) is carried out by methods commonly used in the art as well as by commonly used instruments. The component of step (1) can be hot-melt extruded, for example, using Leistritz ZSE 12 HP-PH-40D.
In one embodiment, the hot melt extrusion temperature of step (2) is about 160±20 ℃.
Preparation of solid formulations
In another aspect, the invention also relates to a method of preparing a solid formulation: which comprises the following steps:
(1) Preparing a pharmaceutical composition according to the above method;
(2) Comminuting the pharmaceutical composition of step (1) to obtain pharmaceutical composition particles;
(3) Mixing the pharmaceutical composition particles of step (2) with a lubricant and other formulation modifiers to obtain total mixed particles;
(4) The total mixed granules of step (3) are pressed to obtain a solid formulation.
Step (2)
The pulverization of step (2) is carried out by a method commonly used in the art. For example, blade pulverization and roll shaft pulverization may be used.
Step (3)
The mixing of step (3) may be carried out by methods commonly used in the art. For example, V-type mixing and hopper mixing may be used.
Step (4)
The pressing of step (4) may be performed using methods commonly used in the art. For example, hydraulic pressing, mechanical pressing, pneumatic pressing, and the like can be used. The equipment that can be used can be, for example, a ZP14 tablet press of the chinese medicine lozenges, etc.
In one embodiment, preparing the solid formulation of the present invention further comprises the steps of:
step (5) coating the solid formulation of step (4) to obtain a tablet.
The coating of step (5) may be carried out using methods commonly used in the art. For example, an Ohara coater or the like can be used.
It should be understood that the above-listed methods of preparing the compositions are merely illustrative and representative. Thus, the methods of preparing the compositions of the present invention are not limited to include only those methods set forth herein above. Various changes, modifications or equivalents may be made to the preparation method according to conventional techniques by those skilled in the art without departing from the scope of the invention.
Pharmaceutical use
The present invention also relates to a method for preventing and treating prostate cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition or solid formulation of the present invention.
The pharmaceutical composition or the solid preparation of the invention can be used for preventing and treating the prostate cancer.
The invention also relates to the use of the pharmaceutical composition or the solid preparation of the invention for preparing medicaments for preventing and treating prostate cancer.
Advantageous effects
Compared with the prior art, the darostaamine pharmaceutical composition of the invention can further improve the solubility of the active ingredient, thereby obtaining the pharmaceutical composition with excellent solubility and effectively improving the bioavailability of the composition. Thus, the darostaamine pharmaceutical composition of the present invention can be administered at a low dose and reduce food effects.
In addition, the darostaamine pharmaceutical composition of the invention has excellent stability, is suitable for normal temperature preservation, and reduces the requirements on storage and transportation.
In addition, the darostamine pharmaceutical composition of the present invention has suitable bulk density and repose angle, which proves that it has good fluidity, so that it is easy to be made into a tablet form, etc., and is suitable for large-scale amplification and industrial production.
Furthermore, by using a proper carrier material and a preparation modifier, compared with the prior art, the darostaamine pharmaceutical composition has obviously improved solubility, solubility and stability; and the obtained medicinal composition particles have improved bulk density and repose angle, and are easier to carry out operations such as pressing and the like to prepare solid preparations, thereby effectively reducing the production energy consumption.
Examples
The following describes the aspects of the invention in further detail with reference to specific examples.
It should be noted that the following examples are only examples for clearly illustrating the technical solution of the present invention, and are not limiting. Other variations or modifications of the above description will be apparent to those of ordinary skill in the art, and it is not necessary or exhaustive of all embodiments, and obvious variations or modifications of the invention are intended to be within the scope of the invention. The instrumentation and reagent materials used herein are commercially available unless otherwise indicated.
Material
Darostaamine: purchased from Shanghai pinus biotechnology limited;
PVP: purchased from the company BASF,
Figure BDA0003377915050000131
VA64；
PVP K30 from Ashland;
hpmcas: purchased from Shin-Etsu company,
Figure BDA0003377915050000132
HPMCP: hypromellose phthalate available from Shin-Etsu corporation;
polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer: purchased from the company BASF,
Figure BDA0003377915050000133
special: purchased from Evonik Degussa company,
Figure BDA0003377915050000134
VE TPGS: available from PMC Isochem, VE TPGS1000;
SLS: purchased from the company BASF,
Figure BDA0003377915050000141
TEC: available from Merck KGaA, TEC.
Determination of solubility
About 200mg of the sample was weighed into a 50ml shake flask and 50ml of medium pH 6.8 was then added. Shaking the flask, mixing, and placing into a shaker, setting the shaker temperature to 37.2 ℃ and the rotation speed to 50rpm. Samples were taken at 4h and filtered through a 0.45 μm filter to collect filtrate. The measurement was performed by means of a high performance liquid chromatography, and the measurement wavelength was 286nm.
Determination of dissolution
In the following examples, dissolution rate measurement of the formulation was performed by USP II method (paddle method) of the united states pharmacopeia, and specific parameters are as follows.
Dissolution method USP II method (Paddle method)
Dissolution medium phosphate buffer at pH 6.8
Volume of medium 1000ml
Rotational speed 75rpm
Temperature (temperature) 37℃±5℃
Analysis of the dissolution samples: the solution obtained in the dissolution test was filtered with a 0.45 μm filter membrane, and the filtrate was collected and measured by high performance liquid chromatography at a measurement wavelength of 260nm.
The content testing method comprises the following steps: the sample to be tested is dissolved in methanol to make the concentration of the darostamine be 100 mug/ml, and the high performance liquid chromatography is adopted for measurement, and the measurement wavelength is 286nm.
The test method of the related substances comprises the following steps: the sample to be tested is dissolved in methanol to make the concentration of the darostamine be 150 mug/ml, and the high performance liquid chromatography is adopted for measuring, and the measuring wavelength is 286nm.
Preparation example
EXAMPLE 1 preparation of a pharmaceutical composition of darostaamine
The particles of the pharmaceutical composition of darostaamine were prepared according to the specific compositions and weight ratios in table 1.
The preparation method comprises the following steps:
the active ingredients and carrier materials were mixed according to the weight ratios of table 1 to obtain a blend. The blend was fed at a constant rate through a powder feeder into a Leistritz ZSE 12HP-PH-40D hot melt extruder and hot melt extruded at a temperature of 160±20 ℃. The extrudate was collected and the extrudate obtained was crushed using a FitzMill L1A crusher, the crushed extrudate being sieved through 80 mesh.
The pharmaceutical compositions 1-1 to 1-15 of darostaamine and the blends 1-1 to 1-15 of active ingredient with carrier materials are obtained according to the above-described methods, respectively.
Table 1 composition of the darostaamine composition
Composition and method for producing the same Active ingredient Carrier material Active ingredients: carrier material
Composition 1-1 Darotamine VA64 1:2
Compositions 1-2 Darotamine VA64 1:3
Compositions 1-3 Darotamine VA64 1:4
Compositions 1-4 Darotamine HPMCAS 1:1
Compositions 1-5 Darotamine HPMCAS 1:2
Compositions 1-6 Darotamine HPMCAS 1:3
Compositions 1-7 Darotamine HPMCAS 1:4
Compositions 1-8 Darotamine HPMCP-HP55 1:2
Compositions 1 to 9 Darotamine HPMCP-HP55 1:3
Compositions 1 to 10 Darotamine Soluplus 1:2
Compositions 1-11 Darotamine Soluplus 1:3
Compositions 1-12 Darotamine Eudragit-L100 1:2
Compositions 1-13 Darotamine Eudragit-L100 1:3
Compositions 1 to 14 Darotamine PVP K30 1:3
Compositions 1 to 15 Darotamine PVP K30 1:4
EXAMPLE 2 preparation of the Darotamine pharmaceutical composition of the invention
The particles of the pharmaceutical composition of darostaamine were prepared according to the specific compositions and weight ratios in table 2.
The preparation method comprises the following steps:
the active ingredients, carrier materials and formulation modifiers were mixed according to the weight ratios of table 2 to obtain blends. The blend was fed at a constant rate through a powder feeder into a Leistritz ZSE12HP-PH-40D hot melt extruder and hot melt extruded at a temperature of 160±20 ℃. The extrudate was collected and the extrudate obtained was crushed using a FitzMill L1A crusher, the crushed extrudate being sieved through 80 mesh.
The pharmaceutical compositions 2-1 to 2-9 of darostamine and the blends 2-1 to 2-9 of active ingredient with carrier material and formulation modifier, respectively, were obtained according to the above-described method.
Table 2 composition of the darostaamine composition
Composition and method for producing the same Active ingredient Carrier material Agent for improving agent Mass ratio
Composition 2-1 Darotamine HPMCAS TPGS 1:2:0.2
Composition 2-2 Darotamine HPMCAS TPGS 1:4:0.5
Compositions 2-3 Darotamine VA64+HPMCAS / 1:0.5:1.5
Compositions 2 to 4 Darotamine VA64+HPMCAS TPGS 1:0.5:1.5:0.2
Compositions 2 to 5 Darotamine HPMCP-HP55 TPGS 1:3:0.1
Compositions 2 to 6 Darotamine Eudragit L100 TEC 1:2:0.15
Compositions 2 to 7 Darotamine Soluplus SLS 1:3:0.1
Compositions 2 to 8 Darotamine PVP K30 SLS 1:4:0.5
Compositions 2 to 9 Darotamine VA64 SLS 1:4:0.5
Example 3 preparation of darostaamine tablets
Darostaamine tablets were prepared according to the specific compositions and weight ratios in table 3.
The method of the darostaamine tablet is as follows:
(1) A pharmaceutical composition of darostaamine was prepared according to the methods of examples 1 and 2, respectively; (2) Mixing the pharmaceutical composition of step (1) with a filler, a disintegrant, and a lubricant to obtain total mixed particles; (3) The total mixed granules of step (2) are compressed by a ZP14 tablet press to obtain darostaamine tablets.
Table 3 composition of darostaamine tablets
Function of Tablet 2-1 Tablet 2-2 Tablets 2-3 Tablets 2-4 Tablets 2-5 Tablets 2-6
Compositions 1-5 - 900 - - - - -
Composition 2-1 - - 960 - - - -
Compositions 2 to 4 - - - 960 - - -
Compositions 2 to 6 - - - - 945 - -
Compositions 2 to 8 - - - - - 1650 -
Compositions 2 to 9 - - - - - - 1650
Microcrystalline cellulose Filler (B) 300 240 240 255 230 230
Croscarmellose sodium Disintegrating agent 74 74 74 74 90 90
Magnesium stearate Lubricant 26 26 26 26 30 30
Test examples
Example 4 determination of the crystalline form of pharmaceutical compositions
The crystal form determination of the pharmaceutical composition comprises polycrystalline powder X-ray diffraction (PXRD) and Differential Scanning Calorimetry (DSC), and is respectively carried out by a Bruker D8 advance instrument (scanning range: 3 DEG to 40 DEG) and a TA Instruments DSC instrument (scanning range: 30 DEG to 250 ℃).
Table 4 crystalline forms of darostaamine compositions
Composition and method for producing the same Crystal form Composition and method for producing the same Crystal form
Composition 1-1 Partially amorphous Compositions 1-13 Amorphous form
Compositions 1-2 Amorphous form Compositions 1 to 14 Amorphous form
Compositions 1-3 Amorphous form Compositions 1 to 15 Amorphous form
Compositions 1-4 Partially amorphous Composition 2-1 Amorphous form
Compositions 1-5 Amorphous form Composition 2-2 Amorphous form
Compositions 1-6 Amorphous form Compositions 2-3 Amorphous form
Compositions 1-7 Is free of certaintyA kind of electronic device with a display unit Compositions 2 to 4 Amorphous form
Compositions 1-8 Amorphous form Compositions 2 to 5 Amorphous form
Compositions 1 to 9 Amorphous form Compositions 2 to 6 Amorphous form
Compositions 1 to 10 Partially amorphous Compositions 2 to 7 Amorphous form
Compositions 1-11 Amorphous form Compositions 2 to 8 Amorphous form
Compositions 1-12 Amorphous form Compositions 2 to 9 Amorphous form
From the crystal form measurement results of table 4, it is known that the pharmaceutical composition prepared from the active ingredient darostaamine and the carrier material can form amorphous particles, thereby improving the solubility of the darostaamine. Meanwhile, the medicinal composition particles are easy to prepare into medicines, are convenient to prepare into solid preparations, and are suitable for large-scale amplification and industrial production.
Example 5 solubility determination of pharmaceutical compositions and blends
The solubilities of the pharmaceutical compositions 1-1 to 1-14, 2-1 to 2-9 and the corresponding blends were measured according to the above methods, respectively, to obtain the solubilities as shown in Table 4 below. In addition, under the above experimental conditions, the solubility of the darostaamine compound was measured to be 24.9 μg/ml.
Table 5 solubility of pharmaceutical compositions and blends
Pharmaceutical composition/blend Solubility of pharmaceutical composition (μg/ml) Solubility of the corresponding blend (μg/ml)
Composition 1-1 107.2 23.9
Compositions 1-2 260.9 24.6
Compositions 1-3 328.5 26.3
Compositions 1-4 142.7 23.4
Compositions 1-5 488.9 24.1
Compositions 1-6 405.6 25.3
Compositions 1-7 421.6 24.9
Compositions 1-8 438.1 23.5
Compositions 1 to 9 406.2 23.1
Compositions 1 to 10 369.2 24.6
Compositions 1-11 307.5 24.7
Compositions 1-12 470.5 23.2
Compositions 1-13 490.8 25.9
Compositions 1 to 14 321.6 24.7
Compositions 1 to 15 394.2 26.8
Composition 2-1 499.6 26.2
Composition 2-2 462.3 28.1
Compositions 2-3 431.2 24.3
Compositions 2 to 4 479.1 25.3
Compositions 2 to 5 427.2 24.1
Compositions 2 to 6 538.2 24.8
Compositions 2 to 7 395.3 28.7
Compositions 2 to 8 416.5 33.5
Compositions 2 to 9 389.6 29.6
As can be seen from the solubility test results of table 5 above, the active ingredient darostaamine was combined with the carrier material, and the obtained darostaamine pharmaceutical composition had significantly improved solubility. Compared to the darostaamine compound (solubility 24.9 μg/ml) and its mixture with carrier materials and/or formulation modifiers, the darostaamine composition has significantly higher solubility, ranging from 107.2 to 490.8 μg/ml.
Further addition of a formulation modifier, such as TPGS, SLS or TEC, to the darostaamine pharmaceutical composition on the basis of compositions 1-1 to 1-15, the darostaamine pharmaceutical composition of the present invention can achieve further improved solubility of 389.6-538.2 μg/ml. From this, it can be seen that the addition of the formulation improver of the present invention to a pharmaceutical composition can further increase the solubility of the darostaamine pharmaceutical composition.
In addition, compositions 2-8 and compositions 2-9 use polyvinylpyrrolidone as a carrier material and sodium lauryl sulfate as a formulation improver. Compositions 2-1 to 2-2 and compositions 2-4 to 2-6 have significantly improved solubility compared to compositions 2-7 to 2-9. It follows that the choice of carrier material and formulation modifier can affect the solubility of the pharmaceutical composition, with appropriate solubility helping to achieve further enhanced solubility of the pharmaceutical composition.
EXAMPLE 6 determination of bulk Density of pharmaceutical compositions
Bulk density of the pharmaceutical composition was determined by a SOTAX TD2 bulk densitometer. The detection results are shown in Table 6 below.
TABLE 6 bulk Density of pharmaceutical compositions
Composition and method for producing the same Bulk Density (g/mL) Composition and method for producing the same Bulk Density (g/mL)
Composition 1-1 0.384 Compositions 1-13 0.415
Compositions 1-2 0.426 Compositions 1 to 14 0.431
Compositions 1-3 0.413 Compositions 1 to 15 0.419
Compositions 1-4 0.411 Composition 2-1 0.451
Compositions 1-5 0.433 Composition 2-2 0.466
Compositions 1-6 0.447 Compositions 2-3 0.429
Compositions 1-7 0.461 Compositions 2 to 4 0.473
Compositions 1-8 0.441 Compositions 2 to 5 0.469
Compositions 1 to 9 0.452 Compositions 2 to 6 0.436
Compositions 1 to 10 0.428 Compositions 2 to 7 0.431
Compositions 1-11 0.446 Compositions 2 to 8 0.429
Compositions 1-12 0.408 Compositions 2 to 9 0.432
As can be seen from the bulk density measurement results of Table 6 above, compositions 2-1 to 2-9 have relatively higher bulk densities of 0.429 to 0.473g/mL, compared to compositions 1-1 to 1-15 (bulk densities of 0.384 to 0.461 g/mL). Therefore, the preparation modifier is added into the pharmaceutical composition, so that the bulk density of the pharmaceutical composition can be further improved, the obtained pharmaceutical composition particles are suitable for tabletting to prepare tablet products, and the energy consumption generated in the production process can be reduced.
EXAMPLE 7 determination of the Angle of repose of pharmaceutical compositions
The angle of repose of the pharmaceutical composition was determined by an angle of repose analyzer model Granutools Granuheap. The detection results are shown in the following table 7.
TABLE 7 Angle of repose for pharmaceutical compositions
Composition and method for producing the same Angle of repose (°) Composition and method for producing the same Angle of repose (°)
Composition 1-1 45 Compositions 1-13 34
Compositions 1-2 35 Compositions 1 to 14 34
Compositions 1-3 34 Compositions 1 to 15 33
Compositions 1-4 37 Composition 2-1 27
Compositions 1-5 32 Composition 2-2 27
Compositions 1-6 31 Compositions 2-3 37
Compositions 1-7 29 Compositions 2 to 4 22
Compositions 1-8 29 Compositions 2 to 5 28
Compositions 1 to 9 31 Compositions 2 to 6 28
Compositions 1 to 10 33 Compositions 2 to 7 31
Compositions 1-11 32 Compositions 2 to 8 32
Compositions 1-12 38 Compositions 2 to 9 31
As can be seen from the angle of repose measurements in Table 7 above, compositions 2-1 to 2-9 have relatively lower angles of repose, 22-37, than compositions 1-1 to 1-15 (bulk density 29-45). Therefore, the preparation modifier is added into the pharmaceutical composition, the repose angle of the composition can be further reduced, the fluidity of the composition is improved, the obtained pharmaceutical composition particles are suitable for tabletting to prepare tablet products, and the energy consumption generated in the production process can be reduced.
In addition, compositions 2-1 to 2 and compositions 2-4 to 2-6 have relatively lower angles of repose than compositions 2-8 and 2-9. It follows that the choice of carrier material and formulation modifier can influence the angle of repose of the pharmaceutical composition, and that suitable carrier materials and formulation modifiers help the composition to achieve a relatively lower angle of repose, thereby further improving the flowability of the composition, making the pharmaceutical composition particles suitable for use in the preparation of formulated products, and reducing the energy consumption of production.
Example 8 stability testing of pharmaceutical compositions
The pharmaceutical composition is affected by external environment (such as temperature, humidity, etc.) during the placement process to the quality of the preparation product, and crystallization and related substance growth are easy to occur, so that the quality of the product is disqualified. To evaluate the stability of the darostaamine pharmaceutical composition, the present invention tested stability under 40 ℃/75% rh acceleration. The specific test method is as follows:
the darostaamine pharmaceutical composition is filled into HDPE bottles and the HDPE bottles are placed in a stability box. The stability drug was removed at the specified time points for testing to obtain the crystalline form status of the composition, the content of the composition and the content of the related substances, and the related data are shown in table 8 below.
Table 8 stability of the darostaamine composition
Figure BDA0003377915050000211
As can be seen from the stability measurements in Table 8 above, after 6 months of storage, the contents of composition 2-1, composition 2-4 and composition 2-9 were all higher than 94.2%, which is significantly higher than that of composition 1-5.
Therefore, compared with the darostaamine pharmaceutical composition 1-5, the pharmaceutical composition 2-1 and the compositions 2-4 to 2-9 obtained by adding the preparation modifier into the pharmaceutical composition have obviously improved stability, and can effectively reduce the generation of related substances. Thus, the pharmaceutical composition obtained by adding the preparation modifier of the invention to the pharmaceutical composition of darostamine can have obviously improved stability.
In addition, after 6 months of storage, the contents of composition 2-1 and composition 2-4 to composition 2-6 were higher than 96.3% compared with compositions 2-7 to 2-9. While the content of compositions 2-7 to 2-9 was less than 96.1%. It follows that the choice of carrier material and formulation modifier can also affect the stability of the pharmaceutical composition, and that suitable carrier materials and formulation modifiers help to achieve relatively higher stability of the composition.
Furthermore, the applicant has unexpectedly found that when hpacas is used as carrier for the darostamine composition, the pharmaceutical composition can obtain a relatively higher stability when the formulation modifier TPGS is added to the pharmaceutical composition. For example, the content of the pharmaceutical composition remains up to 97.1% over 6 months at 40 ℃/75% rh.
EXAMPLE 9 dissolution testing of pharmaceutical compositions
The solubility of darostaamine in phosphate buffer at pH 6.8 was determined according to the method described above, and the test results are shown in table 9 below.
Table 9 dissolution of the darostaamine tablet
Figure BDA0003377915050000221
As can be seen from the dissolution test results of table 9, the darostaamine pharmaceutical composition tablet of the present invention has significantly improved dissolution rate, dissolution rate and dissolution amount of darostaamine as compared with the darostaamine drug substance and the commercially available darostaamine tablet. For example, under the experimental conditions of the present invention, the darostaamine tablet of the present invention releases more than 90% of darostaamine after 30 minutes and up to 97% of darostaamine after 45 minutes in phosphate buffer having pH 6.8.
Thus, the drug composition of the present invention can obtain significantly improved drug dissolution rate by further adding the formulation improver to the darostamine and the drug composition thereof.
EXAMPLE 10 pharmacokinetic Studies of darostaamine tablets
1. Test formulations
Test formulation T: a darostaamine tablet prepared according to the formulation and process of tablets 2-3 in example 3.
Reference formulation R: darotamine tablet (NUBEQA) on the market
2. Test method
2.1 experiment 1
The selected 10 healthy male subjects were randomly divided into 2 groups of 5 persons each using an open, random, bi-periodic, double-cross self-control design method (7 days wash period). The grouping scheme is shown in the following table:
TABLE 10 grouping
Figure BDA0003377915050000231
Subjects entered a phase I clinical trial ward before the test day, had a uniform light diet at night, and then fasted overnight (at least 10 hours, without water deprivation). The subjects took the same dose of darostaamine tablet orally about 8 a.m. after a high fat meal, drinking 240ml of water. No water is needed within 2 hours after taking the medicine, the upper body is kept in an upright state, and unified lunch is carried out after 4 hours.
The blood sample collection method comprises the following steps: 4mL of elbow vein blood of a subject is collected at 0h before administration (within 1h before administration) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12, 24 and 36h after administration, the blood sample is placed in a heparin sodium anticoagulated blood collection tube, centrifugation is carried out at 3500rpm for 5min at 4 ℃ after collection, plasma is divided into two parts, 1mL of plasma is taken and added into a main tube, and the rest plasma is added into a backup tube. The sample is placed in a refrigerator at the temperature of minus 20 ℃ for standby after 2 hours after collection.
The concentration of darostaamine in each plasma sample was determined using LC-MS/MS method.
2.2 experiment 2
The selected 10 healthy male subjects were randomly divided into 2 groups of 5 persons each using an open, random, bi-periodic, double-cross self-control design method (7 days wash period). The grouping scheme is shown in the following table:
TABLE 11 grouping
Figure BDA0003377915050000241
Subjects entered a phase I clinical trial ward before the test day, had a uniform light diet at night, and then fasted overnight (at least 10 hours, without water deprivation). The subjects took the same dose of darostaamine tablet test preparation T orally after a high fat meal or orally on an empty stomach about 8 a day, and consumed 240ml of water as required. No water is needed within 2 hours after taking the medicine, the upper body is kept in an upright state, and unified lunch is carried out after 4 hours.
The blood sample collection method comprises the following steps: 4mL of elbow vein blood of a subject is collected at 0h before administration (within 1h before administration) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12, 24 and 36h after administration, the blood sample is placed in a heparin sodium anticoagulated blood collection tube, centrifugation is carried out at 3500rpm for 5min at 4 ℃ after collection, plasma is divided into two parts, 1mL of plasma is taken and added into a main tube, and the rest plasma is added into a backup tube. The sample is placed in a refrigerator at the temperature of minus 20 ℃ for standby after 2 hours after collection.
The concentration of darostaamine in each plasma sample was determined using LC-MS/MS method.
The foregoing description of the embodiments of the present invention should not be construed as limiting the scope of the invention, but rather should be construed in view of the appended claims, as well as any equivalents thereof, or direct or indirect application in other relevant arts.

Claims (10)

1. A pharmaceutical composition comprising the active ingredient darostamine or a pharmaceutically acceptable salt thereof, a carrier material and a formulation improving agent, wherein
The preparation modifier is one or more selected from the following: sodium lauryl sulfate, polyethylene glycol vitamin E succinate, poloxamer, polyoxyethylene hydrogenated castor oil, stearyl alcohol, dibutyl sebacate, triethyl citrate, butyl citrate, glycerin, polyethylene glycol, lecithin, sodium dioctyl sulfosuccinate, sodium taurocholate, polysorbate, polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, and polyoxyethylene castor oil;
the carrier material is one or more selected from the following: hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl methylcellulose acetate succinate, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, ewing, copovidone, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropyl cellulose, polyvinyl acetate, cyclodextrin, sodium carboxymethyl ethylcellulose polyethylene oxide, cellulose acetate phthalate, cellulose acetate trimellitate.
2. The pharmaceutical composition of claim 1, wherein
The preparation modifier is one or more selected from the following: sodium dodecyl sulfate, vitamin E succinic acid polyethylene glycol ester, and triethyl citrate.
3. The pharmaceutical composition of claim 1 or 2, wherein
The carrier material is one or more selected from the following: hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose acetate succinate, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and Uttky.
4. The pharmaceutical composition of any one of claims 1-3, wherein
The pharmaceutical composition further comprises one or more selected from the group consisting of: buffering agents, acidulants, stabilizers, preservatives;
preferably, the method comprises the steps of,
the buffer is one or more selected from the following: citric acid buffer, malate buffer, maleate buffer, tartrate buffer; and/or
The acidulant is one or more selected from the following: tartaric acid, carbonic acid, acetic acid, oxalic acid, nitrous acid; and/or
The stabilizer is one or more selected from the following: methionine, lysine, histidine;
The preservative is one or more selected from the following: benzyl alcohol, benzyl benzoate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, vitamin E, and vitamin A palmitate.
5. The pharmaceutical composition of any one of claims 1-4, wherein
The weight ratio of active ingredient darostamine or pharmaceutically acceptable salt thereof to carrier material is about 1:0.5-1:8; preferably about 1:1 to 1:4; more preferably from about 1:2 to about 1:4; and/or
The weight ratio of active ingredient darostamine or a pharmaceutically acceptable salt thereof to the formulation modifier is about 1:0.05-1:0.8; preferably about 1:0.1 to about 1:0.5.
6. The pharmaceutical composition of any one of claims 1-5, wherein
The bulk density of the pharmaceutical composition is about 0.40-0.50g/mL; preferably about 0.42-0.49g/mL; more preferably about 0.436-0.473g/mL; and/or
The angle of repose of the pharmaceutical composition is about 20 ° -32 °; preferably about 21 ° -30 °; more preferably about 22 deg. -28 deg..
7. A solid formulation comprising the pharmaceutical composition of any one of claims 1-6.
8. A method of preparing the pharmaceutical composition of any one of claims 1-6, comprising the steps of:
(1) Weighing the components;
(2) Mixing the components of step (1) and hot melt extrusion to obtain a pharmaceutical composition.
9. A method of preparing the solid formulation of claim 7, comprising the steps of:
(1) Preparing a pharmaceutical composition according to the method of claim 8;
(2) Comminuting the pharmaceutical composition of step (1) to obtain pharmaceutical composition particles;
(3) Mixing the pharmaceutical composition particles of step (2) with a lubricant and other formulation modifiers to obtain total mixed particles;
(4) Pressing the total mixed particles of step (3) to obtain a solid formulation;
optionally, the method further comprises the following steps:
(5) Coating the solid formulation of step (4) to obtain a tablet.
10. Use of a pharmaceutical composition according to any one of claims 1 to 6 or a solid formulation according to claim 7 in the manufacture of a medicament for the prophylaxis or treatment of prostate cancer.
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